Shigella type-III secretion system effectors counteract the induction of host inflammation and cell death.

Many enteric bacterial pathogens deliver virulence effectors to counteract host innate immune responses, such as inflammation and cell death, and colonize the intestinal epithelium. However, host cells recognize the disruption of their innate immune signaling by bacterial effectors and induce alternative immune responses, collectively termed "effector-triggered immunity", to clear bacterial pathogens. Here, we describe a mechanism of cell death induction via effector-triggered immunity and the bacterial countermeasures of the pathogen Shigella flexneri. Shigella delivers the OspI effector to inhibit NF-κB activation, which results in caspase-8 activation in return. Deamidation and inactivation of the E2 ubiquitin-conjugating enzyme Ubc13 by OspI results in the inactivation of cIAPs, which serves as a cue to trigger apoptosis and necroptosis. To prevent caspase-8-mediated apoptosis, Shigella delivers OspC1 and inhibits caspase-8 activation via its ADP-riboxanation activity, which however triggers necroptosis. Necroptosis induced as a secondary effector-triggered immunity response by OspC1 is eventually prevented by another Shigella effector, OspD3. The findings of this study reveal a complex multilayered bacterial strategy for circumventing host cell death induction via effector-triggered immunity.